Cyclophosphamide (also known as cytoxan) is one of the most widely used anti-cancer drugs in the world. It is generally administered in combination with a number of other drugs to treat a wide variety of hematologic and solid tumors. However, there are several features of the drug that limit its clinical utility. First, the drug requires cytotoxic activation in the liver to produce metabolities that are toxic to cancer cells. Second, the drug is specifically toxic to the urinary bladder and also displays bone marrow toxicity typical of the alkylating agent class of anti-cancer drugs. Third, cyclophosphamide is a potent suppressor of the immune system at the doses used to treat cancer, thus decreasing the infection-fighting ability of patients already debilitated by their disease. Finally repeated use of cyclophosphamide frequently results in the development of resistance to the drug in a patient's cancer cells, thus rendering the drug ineffective.
The present phosphoramidate compounds circumvent one or more of these problems, because they possess several new, surprising, and highly beneficial properties. First, the present compounds are more cytotoxic under oxygen-deficient conditions than under normal aerobic conditions. Therefore, unlike cyclophosphamide which is cytotoxically activated in the liver, the present compounds become selectively cytotoxic in hypoxic cells. Hence, oxygen-deficient tumor cells are selectively destroyed by concentrations of these compounds which do not affect non-cancerous cells. Second, these compounds are not toxic to the urinary bladder. Third, the compounds of the present invention are effective in treating tumors in animals that have developed resistance to cyclophosphamide.
Therefore, the present compounds represent a substantial improvement over known antitumor agents.